This application is a national stage filing of PCT International Application No. PCT/FI99/01016, filed on Dec. 8, 1999, which published in the English language.
The present invention relates to a new medical use of, and a method of treatment using, toremifene or a pharmaceutically acceptable thereof, for lowering endothelin-1 levels in mammals, and for the prevention or treatment of endothelin mediated diseases.
Endothelin-1 (ET-1) is a 21 amino acid peptide produced by endothelial cells in response to a variety of chemical and mechanical signals. It has a powerful vasoconstrictor and bronchoconstrictor activity and exerts multiple biologic effects. Another endothelium-derived mediator nitric oxide (NO) is in contrast known to be potent vasorelaxing factor. Endothelin-1 (ET-1) is one of three recently identified potent vasoconstricting peptides which also include endothelin-2 and endothelin-3. The molecular structure and biological activities of endothelin were explored in several studies starting soon after its discovery in 1988, but only recently has the availability of specific ET-1 antagonists allowed its physiological activities to be explored.
There is now evidence that the excess production or excess secretion of endothelin is one of the factors responsible for e.g. systemic hypertension, pulmonary hypertension, pulmonary fibrosis, bronchial asthma, acute respiratory distress syndrome, myocardial infarction, thrombosis, congestive heart failure, cardiac hypertrophy, cerebral vasospasm, cerebral infarction, subarachnoidal haemorrhage, vascular dementia, Raynaud""s disease, renal failure, cyclosporin nephrotoxicity, benign prostatic hyperplasia, diabetic angiopathy, gastric ulcer, liver cirrhosis, pancreatitis, migraine, glaucoma, retinopathy, sepsis, organ dysfunction after transplantation, multiple organ failure, preeclampsia and endotoxic shock.
Thus a compound which antagonizes endothelin or inhibits the production or secretion of endothelin has been considered to be useful in the treatment or prevention of the above various diseases.
Toremifene and tamoxifen are triphenylethylene antiestrogens currently used in the treatment of estrogen receptor positive breast cancer. The preparation of toremifene and its salts is described in U.S. Pat. No. 4,696,949. The use of toremifene for the reversal of multidrug resistance of cancer cells to cytotoxic compounds has been described in U.S. Pat. No. 4,990,538. The use of toremifene for treating autoimmune diseases has been described in WO 94/09764. The use of toremifene for sensitizing cancer cells to killer cell mediated lysis is described in WO 95/04544. Finally, the use of toremifene for lowering serum lipid peroxides has been described in WO 97/41847.
It has been found that toremifene or a pharmaceutically acceptable salt thereof is able to lower endothelin levels in mammals. Therefore toremifene or a pharmaceutically acceptable salt thereof is useful in the prevention or treatment of endothelin related conditions such as systemic hypertension, pulmonary hypertension, pulmonary fibrosis, bronchial asthma, acute respiratory distress syndrome, myocardial infarction, thrombosis, congestive heart failure, cardiac hypertrophy, cerebral vasospasm, cerebral infarction, subarachnoidal haemorrhage, vascular dementia, Raynaud""s disease, renal failure, cyclosporin nephrotoxicity, benign prostatic hyperplasia, diabetic angiopathy, gastric ulcer, liver cirrhosis, pancreatitis, migraine, glaucoma, retinopathy, sepsis, organ dysfunction after transplantation, multiple organ failure, preeclampsia and endotoxic shock.